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Paul F. Engstrom, MD
Senior Vice President for Population Science |
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Alison A. Evans, ScD
Associate Member |
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W. Thomas London, MD
Senior Member |
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Alison A. Evans, ScD, Associate Member
W. Thomas London, MD, Senior Member
Paul F. Engstrom, MD, Senior Vice President for Population Science
Fox Chase Cancer Center
Philadelphia, Pennsylvania
Hepatocellular carcinoma (HCC) has become a disease of increasing importance in the US and other Western countries. Although the areas of highest incidence globally are in East Asia and subSaharan Africa, HCC incidence has increased in North America and Western Europe in recent years. (1) Surveillance, Epidemiology, and End Results (SEER) data show a doubling of HCC incidence rates in the US between 1985 and 1998, reaching 4.1 per 100,000 persons by the year 2000, with a proportionally greater increase in the incidence rates in younger age groups. (2)
Worldwide, liver cancer is the third most common cause of cancer mortality, with approximately 550,000 annual deaths. (3) The American Cancer Society estimates 14,270 deaths from liver cancer in the US in 2004, of which 70%--80% were HCC. Liver cancer is the eighth most frequent cause of cancer mortality in US men and the twelfth in women. (4) The highest incidence rates are found among Asian-Americans, who have about double the risk of African-Americans and Hispanics and four times the risk of Caucasians. (2)
Chronic infection with hepatitis C virus (HCV) and/or hepatitis B virus (HBV) is associated with the majority of HCC cases. Recent estimates for the US have attributed 47% of cases to HCV alone, 15% to HBV alone, and 5% to coinfection with both viruses. (5) The remaining 33% of cases appear to be due to nonviral causes. Internationally, HBV is responsible for a far greater proportion of HCC cases than it is in the US, reflecting the higher prevalence of HBV in many developing countries.
Except for the fact that both are hepatotropic viruses that can cause chronic infections, there are few biological similarities between HCV and HBV (Table 1 summarizes the characteristics of HCV and HBV as risk factors for HCC). Both can cause infections of long duration (often lasting many decades), which lead to chronic active hepatitis and liver cirrhosis. Increased hepatocyte death and proliferation occurs and fibrosis may develop. Ongoing inflammation results in the production of DNA-damaging reactive oxygen intermediates. (6) Specific genetic alterations common to all HCCs have not yet been identified. Chromosomal and genetic abnormalities in these tumors are widespread, but a few common sites of chromosomal alteration have been identified. (7)
Table 1
Comparison of HCV and HBV as Risk Factors for HCC
|
HCV |
HBV |
| Number chronically infected (US) |
2.7 million |
1.3 million |
| Number chronically infected (world) |
170 million |
350 million |
| Lifetime risk of HCC if chronically infected |
~10%--25% |
~1%--5% |
| Number of associated HCC cases/year (US) |
~5,000-5,600 |
~1,800-2,000 |
| Virus |
Single stranded RNAdoes not integrate |
Partially double stranded DNAintegrates in host genome |
| Prevalence of cirrhosis in HCC |
~100% |
~80%--90% |
| Time from infection to HCC |
20--30 years, shorter with older age at infection |
20--70 years, varies by population |
| Prevention strategies |
Infection control, anti-viral therapies, early detection |
Infection control, vaccination, anti-viral therapies, early detection |
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HCV = hepatitis C virus; HBV = hepatitis B virus; HCC = hepatocellular carcinoma.
HCV is a single-stranded RNA virus of the flavivirus family, about 9.5 kb in length. HCV does not integrate into the host genome, and the means by which it establishes chronic infection are unknown. The association of chronic HCV infection with development of HCC is well-established; this nearly always occurs in the presence of cirrhosis. It is estimated that approximately 80% of persons infected with HCV will develop a chronic infection, and 15%--20% will develop serious liver disease, often many decades later. Among those who develop cirrhosis, 1%--4% per year will develop HCC. Several important cofactors, such as alcohol consumption and older age at infection, are known to affect the probability of developing HCC among persons chronically infected with HCV.
(8-10)
HBV is a small, partially double-stranded DNA virus of the hepadnavirus family, which replicates through a reverse transcription phase. Unlike HCV, HBV integrates into the host hepatocyte genome early in infection, usually at sites of DNA damage. (11) The virus carries no known oncogenes, and sites of integration are not consistent from cell to cell. But the presence of multiple integrated viral genes is thought to create genomic instability in the host and may lead to loss of heterozygosity for tumor suppressor genes. Moreover, hepatitis B x antigen acts as a transactivator that may lead to increased transcriptional activity of cellular oncogenes as well as interference with the function of tumor suppressor genes, such as p53.(6) In populations where HBV infection occurs in early childhood, the lifetime risk of HCC in an HBV-infected person has been estimated at 27% for males and 4% for females. (12) Among endemic populations, however, there may be substantial disparities in HCC risk due to differences in the natural history of chronic HBV infection between populations. (13) In persons infected later in life, it is possible that risks are somewhat lower but few studies have been able to address this issue.
The most effective means available for prevention of viral hepatitis-associated HCC is prevention of the initial viral infection. A vaccine against HBV has been available since 1982, and early childhood vaccination programs have been the most effective strategy for reducing the prevalence of infection, particularly in high-risk populations. The global impact of childhood HBV infection programs is beginning to be seen. In Taiwan, where universal newborn vaccination began in 1984, HCC incidence rates have begun to decline in young people. (14) In the US, universal infant HBV vaccination has been recommended since 1991 after the previous strategy of targeting only high-risk individuals failed to reduce the incidence of HBV infection. (15) Prevention of HCV infection is more difficult due to the lack of a vaccine or effective post-exposure prophylaxis. Universal precautions against exposure to bloodborne infectious agents are the primary means of prevention. In the US, these measures have led to a reduction in the number of new infections per year from an average of 240,000 in the 1980s to about 25,000 in 2001. (16)
Effective secondary prevention of HCC depends upon early detection of small tumors. The most commonly used serum marker, alphafetoprotein, is a fetal antigen produced by 40%--80% of HCCs. Patients with chronic viral hepatitis or cirrhosis of any etiology are candidates for semiannual or annual screening with alphafetoprotein, with ultrasonographic follow-up of those with elevated levels. (17) Such screening programs have shown that identification of small, asymptomatic lesions is possible, but a consequent reduction in HCC mortality has not always been evident. The cost-benefit ratio of alphafetoprotein plus ultrasound screening versus ultrasound alone is still a subject of debate and may depend upon risk factors in the population. (18) Particularly in studies of Western populations, the addition of alphafetoprotein testing has not always been shown to improve the performance of ultrasound screening alone, (19-20) but most current guidelines continue to recommend the use of both screening modalities.
Antiviral therapies for both HCV and HBV have shown promise in the reduction of HCC risk for those whose disease is amenable to such treatment. (21) Current antivirals, however, are not effective in all chronically infected persons and are generally most useful in those who already have biochemical and/or histologic evidence of active liver disease. Cancer chemoprevention strategies that focus on other portions of the etiologic pathways for HCC may be a fruitful avenue for future prevention efforts, particularly in the reduction of immune-mediated liver damage.
At present there are estimated to be 2.7 million Americans chronically infected with HCV (22) and 1.3 million chronically infected with HBV. (23) These individuals are at high risk for the occurrence of HCC, a disease for which long term survival rates are poor. The development of cancer prevention programs targeting this population may be the best hope to reduce the increasing public health impact of HCC.
References
- McGlynn KA, Tsao L, Hsing AW, et al. International trends and patterns of primary liver cancer. Int J Cancer. 2001;94:290-296.
- El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004;127:S27-S34.
- Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001;37:S4-S66.
- American Cancer Society. Cancer Facts and Figures - 2004. Atlanta: American Cancer Society, 2004:60.
- Di Bisceglie AM, Lyra AC, Schwartz M, et al. Hepatitis C-related hepatocellular carcinoma in the United States: influence of ethnic status. Am J Gastroenterology. 2003;98:2060-2063.
- Feitelson MA, Sun B, Satiroglu Tufan NLS, et al. Genetic mechanisms of hepatocarcinogenesis. Oncogene. 2002; 21:2593-2604.
- Balsara BR, Pei J, De Rienzo A, et al. Human hepatocellular carcinoma is characterized by a highly consistent pattern of genomic imbalances, including frequent loss of 16q23.1-24.1. Genes Chromosomes & Cancer. 2001;30:245-253.
- Ikeda K, Saitoh S, Koida I, et al. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology. 1993;18:47-53.
- Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345:41-52.
- Tsukuma H, Hiyama T, Tanaka S, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med. 1993;328:1797-1801.
- Bill CA, Summers J. Genomic DNA double-strand breaks are targets for hepadnaviral DNA integration. Proceedings of the National Academy of Sciences of the United States of America 2004; 101:11135-11140.
- Dickinson JA, Wun WT, Wong SL. Modeling death rates for carriers of hepatitis B. Epidemiology and Infection. 2002;128:83-92.
- Evans AA, O'Connell AP, Pugh JC, et al. Geographic variation in viral load among hepatitis B carriers with differing risks of hepatocellular carcinoma. Cancer Epidemiol Biomarkers. 1998;7:559-565.
- Chang M-H, Shau W-Y, Chen C-J, et al. Hepatitis B vaccination and hepatocellular carcinoma rates in boys and girls. JAMA. 2000;284:3040-3042.
- Centers for Disease Control. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morbidity & Mortality Weekly Report 1991;40:1-25.
- Centers for Disease Control and Prevention. Viral hepatitis C fact sheet. Vol. 2004: National Center for Infectious Diseases,
www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm, 2004.
- Colombo M. Screening for cancer in viral hepatitis. Clin Liver Dis. 2001;5:109-123.
- Sherman M. Alphafetoprotein: an obituary. J Hepatol. 2001;34:603-605.
- Cottone M, Turri M, Caltagirone M, et al. Screening for hepatocellular carcinoma with Child’s A cirrhosis: an 8-year prospective study by ultrasound and alphafetoprotein. J Hepatol. 1994;21:1029-1034.
- Solmi L, Primerano AM, Gandolfi L. Ultrasound follow-up of patients at risk for hepatocellular carcinoma: results of a prospective study on 360 cases. A J Gastroenterol. 1996;91:1189-1194.
- Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531.
- Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-562.
- Lok ASF, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857-861.
